Xcopri

/ Dexcel

Adults: The recommended starting dose of cenobamate is 12.5 mg per day, titrated gradually to the recommended target dose of 200 mg per day. Based on clinical response, dose may be increased to a maximum of 400 mg per day. See prescribing information for the recommended titration schedule, which should not be exceeded because of the potential for serious adverse reactions.
Elderly (65 years of age and above): Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic or renal function and of concomitant disease as well as the potential interactions in polymedicated patients.
Renal impairment: Cenobamate should be used with caution and reduction of the target dose may be considered in patients with mild to moderate (creatinine clearance 30 to <90 ml/min) or severe (creatinine clearance < 30 ml/min) renal impairment. The maximum recommended dose for patients with mild, moderate, or severe renal impairment is 300 mg/day. Cenobamate should not be used in patients with end-stage renal disease or patients undergoing haemodialysis.
Hepatic impairment: Exposure to cenobamate was increased in patients with chronic hepatic disease. A change in the starting dose is not required; however, a decrease in target doses of up to 50% may need to be considered. The maximum recommended dose in patients with mild and moderate hepatic impairment is 200 mg/day. Cenobamate should not be used in patients with severe hepatic impairment.
Paediatric population: The safety and efficacy in children aged 0 months to 18 years have not yet been established. No data are available.
See prescribing information for full details.

For the adjunctive treatment of focal-onset seizures with or without secondary generalization in adult patients with epilepsy who have not been adequately controlled despite a history of treatment with at least 2 anti-epileptic medicinal products.

*Hypersensitivity to the active substance or to any of the excipients.
*Familial Short-QT syndrome.

Suicidal ideation
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic medicinal products in several indications. Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered.
Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Drug reaction with eosinophilia and systemic symptoms (DRESS)
Drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, has been reported in association with cenobamate when started at higher doses and titrated rapidly (weekly or faster titration). When cenobamate was initiated at 12.5 mg/day and titrated every two weeks, in an open-label safety study of 1,340 epilepsy patients, no cases of DRESS were reported. At the time of prescription, patients should be advised of the signs and symptoms of DRESS and monitored closely for skin reactions. Symptoms of DRESS include typically, although not exclusively, fever, rash associated with other organ system involvement, lymphadenopathy, liver function tests abnormalities and eosinophilia. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If signs and symptoms suggestive of these reactions appear, cenobamate should be withdrawn immediately and an alternative treatment considered (as appropriate).
QT-shortening
A dose-dependent shortening of the QTcF interval has been observed with cenobamate.
In clinical trials there was no evidence that the combination of cenobamate with other antiepileptic medicines led to further QT- shortening. Clinicians should use caution when prescribing cenobamate in combination with other medicinal products that are known to shorten the QT.
Familial Short QT syndrome is a rare genetic syndrome, which is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Cenobamate must not be used in patients with Familial Short-QT syndrome.
Contains lactose
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
See prescribing information for full details.

Common: confusional state, irritability, dysarthria, nystagmus, aphasia, memory impairment, diplopia, vision blurred, constipation, diarrhea, nausea, vomiting, dry mouth, rash, hepatic enzyme increased.
Very common: somnolence, coordination and gait abnormalities, and headache.
See prescribing information for full details.

Cenobamate is extensively metabolized, primarily by glucuronidation, with oxidation contributing to a lesser degree.
Cenobamate may reduce exposures of products primarily metabolized by CYP3A4 and 2B6. Cenobamate may increase exposures of products primarily metabolized by CYP2C19. When initiating or discontinuing treatment with cenobamate or changing the dose, it may take 2 weeks to reach the new level of enzyme activity.
Pharmacodynamic interactions
CNS depressants
Concomitant use of cenobamate with other CNS depressants, including alcohol, barbiturates, and benzodiazepines may increase the risk of neurological adverse reactions. Therefore, based on individual response, doses of barbiturates and benzodiazepines may need to be reduced, as clinically appropriate, when used concomitantly with cenobamate.
Interactions with other antiepileptics
Phenytoin– In a study in healthy subjects, concomitant administration of cenobamate 200 mg/day and phenytoin 300 mg/day slightly reduced cenobamate exposures (Cmax by -27%, AUC by -28%), and increased phenytoin exposures (Cmax by 67%, AUC by 84%). No dose adjustment of cenobamate is required. Phenytoin concentrations should be monitored during titration of cenobamate, and based on individual response, the dose of phenytoin may need to be reduced.
Phenobarbital– In a study in healthy subjects, concomitant administration of cenobamate 200 mg/day and phenobarbital 90 mg/day did not cause clinically meaningful changes in cenobamate exposure but led to increased phenobarbital exposures (Cmax by 34% and AUC by 37%). No dose adjustment of cenobamate is required. Concentrations of phenobarbital should be monitored during cenobamate titration, and based on individual response, the dose of phenobarbital may need to be reduced.
Clobazam– Pharmacometric analyses of data from healthy subjects and patients predict that clobazam slightly increases cenobamate exposures (by 24%). No dose adjustment of cenobamate is required. Due to a possible increase in exposure of the active metabolite of clobazam (N-desmethylclobazam), related to the induction of CYP3A4 (formation) and the inhibition of CYP2C19 (elimination), the dose of clobazam may need to be reduced.
Lamotrigine– Pharmacometric analyses of data from healthy subjects and patients showed that concomitant administration of cenobamate with lamotrigine had no effect on cenobamate exposures, but resulted in dose-dependent decreases in lamotrigine concentrations (by -21%, -35%, and -52% for cenobamate 100, 200, and 400 mg/day). Based on subpopulation analyses of patients taking concomitant lamotrigine, higher doses (200 – 400 mg/day) of cenobamate may be required for efficacy when co- administered with lamotrigine. Depending on individual response, the dose of cenobamate may need to be increased.
Carbamazepine- No clinically meaningful decreases in efficacy were observed in subpopulation analyses of patients taking concomitant carbamazepine. Therefore, no dose adjustments are required.
Valproic acid- Pharmacometric analyses of data from healthy subjects and patients indicated that concomitant administration of cenobamate with valproic acid did not affect cenobamate exposures and had no clinically relevant reductions in valproic acid concentration. No dose adjustments are required.
Concomitant administration with lacosamide, levetiracetam, or oxcarbazepine did not affect the exposure of cenobamate. No dose adjustments are required for cenobamate, lacosamide, levetiracetam, or oxcarbazepine.
Other medicinal products
Oral contraceptives
Since hormonal contraceptives may also be metabolized by CYP3A4, their efficacy may be reduced by concomitant use with cenobamate. Therefore, women of reproductive potential concomitantly using oral contraceptives should practice additional or alternative non-hormonal measures of birth control.
CYP3A4 substrates
An increase in the dose of medicines metabolized by CYP3A4 may be required when used concomitantly with cenobamate.
CYP2B6 substrates
An increase in the dose of medicines metabolized by CYP2B6 may be required when used concomitantly with cenobamate.
CYP2C19 substrates
A dose reduction of medicines metabolized by CYP2C19 may be required when used concomitantly with cenobamate.
OAT3 substrates
In vitro studies have shown that cenobamate inhibits OAT3, a transporter predominantly involved in the elimination of certain medicines (e.g. baricitinib, cefaclor, empagliflozin, penicillin G, ritobegron, and sitagliptin). Therefore, concomitant administration of cenobamate and medicinal products transported by OAT3 may result in higher exposure of these medicinal products.
See prescribing information for full details.

Women of childbearing potential and contraception in males and females
Cenobamate is not recommended in women of childbearing potential not using contraception. Women of reproductive potential concomitantly using oral contraceptives should practice additional or alternative non-hormonal measures of birth control during treatment with cenobamate and until 4 weeks after treatment discontinuation.
Pregnancy
Risk related to epilepsy and antiepileptic medicinal products in general.
It has been shown that in the offspring of treated women with epilepsy, the prevalence of malformations is two to three times greater than the rate of approximately 3% in the general population. In the treated population, an increase in malformations has been noted with polytherapy; however, the extent to which the treatment and/or the underlying condition is responsible has not been elucidated. Discontinuation of anti-epileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus.
There are no adequate data from the use of this medical product in pregnant women.
Women of childbearing potential must use effective contraception during use of cenobamate and until 4 weeks after treatment discontinuation.
Breast-feeding
It is unknown whether cenobamate or its metabolites are excreted in human milk.
A risk to the suckling child cannot be excluded. As a precautionary measure, breast-feeding should be discontinued during treatment.
Fertility
The effects of cenobamate on human fertility are unknown.

Symptoms of overdose are expected to be consistent with the known adverse reactions of this medical product and include somnolence, fatigue, dizziness. There is no available specific antidote to the effects of cenobamate. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient.